Abstract

Spaceflight stressors may increase Parkinson's disease (PD) risk, but microgravity-specific contribution to human dopaminergic (DA) vulnerability remains undefined. Here, we exposed human iPSC-derived midbrain DA organoids and differentiated SH-SY5Y neurons to simulated microgravity for 72 hours. This exposure reduced neurite outgrowth, eroded DA identity, and activated familial-PD mitochondrial kinases without depleting extracellular dopamine. We observed severe mitochondrial dysfunction-including membrane potential loss and respiratory suppression-coupled with global translational repression. Furthermore, a sublethal, pre-degenerative state emerged, characterized by the selective release of mitochondrial cell-free DNA without apoptotic activation. Proteomic profiling revealed striking convergence with human PD transcriptomes and astronaut blood, highlighting shared suppression of mitochondrial metabolism, ribosomal translation, and altered RNA splicing. Together, these findings establish simulated microgravity as a sufficient, non-toxin trigger of early PD-like DA dysfunction, providing a robust human model for investigating prodromal neurodegeneration.